scholarly journals Genetic variant in 3’ untranslated region of the mouse pycard gene regulates inflammasome activity

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Brian Ritchey ◽  
Qimin Hai ◽  
Juying Han ◽  
John Barnard ◽  
Jonathan D Smith
Keyword(s):  
Mrna Stability ◽  
Untranslated Region ◽  
Embryonic Stem ◽  
Adaptor Protein ◽  
Base Change ◽  
Single Nucleotide ◽  
Single Base Change ◽  
Trait Locus ◽  
Locus Mapping ◽  
Inflammasome Activity

Quantitative trait locus mapping for interleukin-1β release after inflammasome priming and activation was performed on bone-marrow-derived macrophages (BMDM) from an AKRxDBA/2 mouse strain intercross. The strongest associated locus mapped very close to the Pycard gene on chromosome 7, which codes for the inflammasome adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC). The DBA/2 and AKR Pycard genes only differ at a single-nucleotide polymorphism (SNP) in their 3’ untranslated region (UTR). DBA/2 vs. AKR BMDM had increased levels of Pycard mRNA expression and ASC protein, and increased inflammasome speck formation, which was associated with increased Pycard mRNA stability without an increased transcription rate. CRISPR/Cas9 gene editing was performed on DBA/2 embryonic stem cells to change the Pycard 3’UTR SNP from the DBA/2 to the AKR allele. This single base change significantly reduced Pycard expression and inflammasome activity after cells were differentiated into macrophages due to reduced Pycard mRNA stability.

scholarly journals Genetic Variant in 3’ Untranslated Region of the Mouse Pycard Gene Regulates Inflammasome Activity

2021 ◽  
Author(s):  
Brian Ritchey ◽  
Qimin Hai ◽  
Juying Han ◽  
John Barnard ◽  
Jonathan D. Smith
Keyword(s):  
Mrna Stability ◽  
Untranslated Region ◽  
Embryonic Stem ◽  
Adaptor Protein ◽  
Base Change ◽  
Single Nucleotide ◽  
Single Base Change ◽  
Trait Locus ◽  
Locus Mapping ◽  
Inflammasome Activity

AbstractQuantitative trait locus mapping for interleukin-1β release after inflammasome priming and activation was performed on bone marrow-derived macrophages (BMDM) from an AKRxDBA/2 strain intercross. The strongest associated locus mapped very close to the Pycard gene on chromosome 7, which codes for the inflammasome adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC). The DBA/2 and AKR Pycard genes only differ at single nucleotide polymorphism (SNP) in their 3’ untranslated region (UTR). DBA/2 vs. AKR BMDM had increased levels of Pycard mRNA expression and ASC protein, and increased inflammasome speck formation, which was associated with increased Pycard mRNA stability without an increased transcription rate. CRIPSR/Cas9 gene editing was performed on DBA/2 embryonic stem cells to change the Pycard 3’UTR SNP from the DBA/2 to the AKR allele. This single base change significantly reduced Pycard expression and inflammasome activity after cells were differentiated into macrophages due to reduced Pycard mRNA stability.

scholarly journals Genetic evidence for interaction between Cbp1 and specific nucleotides in the 5' untranslated region of mitochondrial cytochrome b mRNA in Saccharomyces cerevisiae.

1997 ◽  
Vol 17 (11) ◽  
pp. 6203-6211 ◽  
Author(s):  
W Chen ◽  
C L Dieckmann
Keyword(s):  
Cytochrome B ◽  
Mrna Stability ◽  
Untranslated Region ◽  
Base Change ◽  
Genetic Evidence ◽  
Site Directed Mutagenesis ◽  
Cis Element ◽  
Mitochondrial Cytochrome B ◽  
Single Base Change ◽  
Cytochrome B Mrna

The cytochrome b (COB) gene is encoded by the mitochondrial genome; however, its expression requires the participation of several nuclearly encoded protein factors. The yeast Cbp1 protein, which is encoded by the nuclear CBP1 gene, is required for the stabilization of COB mRNA. A previous deletion analysis identified an 11-nucleotide-long sequence within the 5' untranslated region of COB mRNA that is important for Cbp1-dependent COB mRNA stability. In the present study, site-directed mutagenesis experiments were carried out to define further the features of this cis element. The CCG sequence within this region was shown to be necessary for stability. A change in residue 533 of Cbp1 from aspartate to tyrosine suppresses the effects of a single-base change in the CCG element. This is strong genetic evidence that the nuclearly encoded Cbp1 protein recognizes and binds directly to the sequence containing CCG and thus protects COB mRNA from degradation.

scholarly journals A gain-of-function single nucleotide variant creates a new promoter which acts as an orientation-dependent enhancer-blocker

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yavor K. Bozhilov ◽  
Damien J. Downes ◽  
Jelena Telenius ◽  
A. Marieke Oudelaar ◽  
Emmanuel N. Olivier ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Diseases ◽  
Regulatory Elements ◽  
Base Change ◽  
Dependent Manner ◽  
Globin Genes ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Super Enhancer ◽  
Single Base Change

AbstractMany single nucleotide variants (SNVs) associated with human traits and genetic diseases are thought to alter the activity of existing regulatory elements. Some SNVs may also create entirely new regulatory elements which change gene expression, but the mechanism by which they do so is largely unknown. Here we show that a single base change in an otherwise unremarkable region of the human α-globin cluster creates an entirely new promoter and an associated unidirectional transcript. This SNV downregulates α-globin expression causing α-thalassaemia. Of note, the new promoter lying between the α-globin genes and their associated super-enhancer disrupts their interaction in an orientation-dependent manner. Together these observations show how both the order and orientation of the fundamental elements of the genome determine patterns of gene expression and support the concept that active genes may act to disrupt enhancer-promoter interactions in mammals as in Drosophila. Finally, these findings should prompt others to fully evaluate SNVs lying outside of known regulatory elements as causing changes in gene expression by creating new regulatory elements.

scholarly journals Unique Temperature-Sensitive Defect in Vaccinia Virus Morphogenesis Maps to a Single Nucleotide Substitution in the A30L Gene

2001 ◽  
Vol 75 (22) ◽  
pp. 11222-11226 ◽  
Author(s):  
Patricia Szajner ◽  
Andrea S. Weisberg ◽  
Bernard Moss
Keyword(s):  
Vaccinia Virus ◽  
Nucleotide Substitution ◽  
Elevated Temperatures ◽  
Base Change ◽  
Temperature Sensitive ◽  
Single Nucleotide ◽  
Reading Frame ◽  
Genetic Lesion ◽  
Virus Morphogenesis ◽  
Single Base Change

ABSTRACT Marker rescue experiments demonstrated that the genetic lesion of a previously isolated vaccinia virus temperature-sensitive mutant which forms multilayered envelope structures with lucent interiors and foci of viroplasm with dense centers mapped to the A30L open reading frame. A single base change, resulting in a nonconservative Ser-to-Phe substitution at residue 17, was associated with degradation of the A30L protein at elevated temperatures.

scholarly journals Suppressor Analysis of Mutations in the 5′-Untranslated Region of COB mRNA Identifies Components of General Pathways for Mitochondrial mRNA Processing and Decay in Saccharomyces cerevisiae

Genetics ◽  
1999 ◽  
Vol 151 (4) ◽  
pp. 1315-1325
Author(s):  
Wei Chen ◽  
Maria A Islas-Osuna ◽  
Carol L Dieckmann
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Untranslated Region ◽  
Mitochondrial Rna ◽  
Rna Turnover ◽  
Single Nucleotide ◽  
Mrna Stabilization ◽  
Recessive Mutations ◽  
A Subunit ◽  
Suppressor Analysis ◽  
Dominant Suppressor

Abstract The cytochrome b gene in Saccharomyces cerevisiae, COB, is encoded by the mitochondrial genome. Nuclear-encoded Cbp1 protein is required specifically for COB mRNA stabilization. Cbp1 interacts with a CCG element in a 64-nucleotide sequence in the 5′-untranslated region of COB mRNA. Mutation of any nucleotide in the CCG causes the same phenotype as cbp1 mutations, i.e., destabilization of both COB precursor and mature message. In this study, eleven nuclear suppressors of single-nucleotide mutations in CCG were isolated and characterized. One dominant suppressor is in CBP1, while the other 10 semidominant suppressors define five distinct linkage groups. One group of four mutations is in PET127, which is required for 5′ end processing of several mitochondrial mRNAs. Another mutation is linked to DSS1, which is a subunit of mitochondrial 3′ → 5′ exoribonuclease. A mutation linked to the SOC1 gene, previously defined by recessive mutations that suppress cbp1 ts alleles and stabilize many mitochondrial mRNAs, was also isolated. We hypothesize that the products of the two uncharacterized genes also affect mitochondrial RNA turnover.

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